Urinary incontinence is a prevalent problem that affects people of all ages and levels of physical health, both in healthcare settings and in the community at large. At present, urinary incontinence afflicts 15-30% of elderly people living at home, one-third of those living in acute-care settings, and at least one-half of those in long-term care institutions (R. M. Resnick, Lancet 346:94 (1995)). Medically, it predisposes persons to urinary tract infections, pressure ulcers, perineal rashes, and urosepsis. Psychosocially, urinary incontinence is associated with embarrassment, social stigmatization, depression, and with the risk of institutionalization (Herzo et al., Annu. Rev. Gerontol. Geriatr., 9:74 (1989)). Economically, the costs are great; in the United States alone, over $10 billion is spent per annum managing incontinence.
Treatments for incontinence include drugs with bladder relaxant properties, i.e., which help to control bladder detrusor muscle overactivity. Such drugs are effective in 80 to 85% of patients with uninhibited bladder contractions, with anticholinergic medications representing the mainstay of this type of treatment. For example, anticholinergics such as propantheline bromide, and combination smooth muscle relaxant/anticholinergics such as racemic oxybutynin and dicyclomine, have been used to treat urge incontinence. (See, e.g., A. J. Wein, Urol. Clin. N. Am., 22:557-77 (1995).)
Another anticholinergic drug, glycopyrrolate, 3-[(Cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide, has also been described for use in the treatment of incontinence (Levin et al., J. Urol., 128:396-398 (1982); Cooke et al., S. Afr. Med. J., 63:3 (1983); R. K. Mirakhur and J. W. Dundee, Anaesthesia, 38:1195-1204 (1983)). Glycopyrrolate has two centers of asymmetry (chiral centers), and can exist in four stereoisometric forms, i.e., two enantiomeric pairs of diastereomers. The two diastereomer pairs have been separated from one another (see, e.g., Demian et al., J. Liq. Chromatog., 13:779-787 (1990)). However, separation of the diastereomers to their individual enantiomers has not been reported, and commercially available formulations of glycopyrrolate (e.g., Robinul.RTM., a product of A. H. Robins) contain both the (R,S)-glycopyrrolate and (S,R)-glycopyrrolate enantiomers.
No treatment for incontinence, including existing drug therapies, has achieved complete success with all classes of incontinent patients, and without significant side effects. For example, adverse effects, such as drowsiness, dry mouth, constipation, blurred vision, headaches, and cardiac arrhythmia which are related to the anticholinergic activity of drugs such as racemic oxybutynin, occur frequently and can be sufficiently troublesome to necessitate discontinuing treatment in up to 25% of patients, depending on the dosage. Yet, despite the occurrence of unwanted anticholinergic effects in many patients, and an apparent lack of efficacy in the elderly institutionalized population, racemic oxybutynin nevertheless is considered the drug of first choice in patients with bladder detrusor muscle hyperactivity when pharmacological therapy is indicated (cf. Yarllur et al., Drugs Aging, 6:243 (1995)). Similar side effects resulting from the use of glycopyrrolate are also described in the literature. (Cf. Physician's Desk Reference, 50th Edition, pages 2072-2073 (1996).)